Effect of Repeated Low-level Red Light on Myopia Prevention Among Children in China With Premyopia

Key Points Question Does a repeated low-level red-light (RLRL) intervention prevent incident myopia among children with premyopia? Findings In this randomized clinical trial including 278 school-aged children with premyopia, the incidence of myopia was lower among children receiving RLRL therapy than among controls. Meaning Exposure to RLRL is a novel and effective intervention for myopia prevention among children with premyopia, with good user acceptability and safety.


Summary Purpose and Principle
A randomized controlled trial exploring the effectiveness of low-dose single-wavelength red light on the prevention of myopia and the decrease of myopia incidence rate in children of grade 1-4 of primary schools (age of 6-11 years).

Primary Objective
To investigate the efficacy of low-level red-light of reducing myopia onset in premyopic children.

Secondary Objective
To investigate the effect of low-level red-light on spherical equivalent, axial length, uncorrected visual acuity of premyopic children.

Study Design
Randomized controlled trial

Study Population
Students of grades 1-4 in the participating schools in Shanghai Inclusion Criteria 1) Students of grades 1-4 in the participating schools.
2) Sign informed consent to participate in screening and follow-up.

Exclusion Criteria
1) Inability to obtain informed consent.
2) Children have astigmatism of 1.50 D or more, anisometropia of 1.50 D or more, strabismus, amblyopia, binocular vision abnormalities and other ocular abnormalities.
3) Children have any systemic diseases. 4) Children have any history of any myopia prevention interventions (e.g., low dose atropine). 5) Children have other reasons that the study physician considers inappropriate for inclusion in the project.

Baseline and Follow-up of Eye Examination
The baseline examination is in April 2021. The follow-up visits are in July 2021, October 2021, and January 2022. A total of five time points are examined in April 2022.

Study Duration
The baseline examination is in April 2021 , and the follow-up will be finished in April 2022. The study lasts for 12 months.

Group
Children in the intervention group receive low-level red-light therapy 5 days per week and twice per day with each session lasting 3 minutes and an interval of at least 4 hours between.

Group
Children in the control group do not receive low-level red-light therapy but continued their usual daily activities.

Study background and principle 43
Myopia is the most common refractive error. It has been epidemic worldwide, especially in 44 East Asia. China has one of the highest myopia prevalence among adolescents in the world, 45 with 15%-80% 1,2 of urban-dwelling adolescents, which is 1.5-5.6 times higher than that in 46 Chile 3 and 11.4-30.8 times higher than that in Nepal 4 . According to the World Health 47 Organization, myopia has become one of the leading causes of visual impairment worldwide. 48 The high cost of optical measurement or surgery for myopia correction each year places a 49 heavy burden on society. Preventing myopia and controlling myopia progression has become 50 a public health problem which needs to be addressed. 51 In order to effectively strengthen the prevention and control of myopia among children and 52 adolescents in China, the Ministry of Education, together with eight departments including the 53 National Health Commission, formulated the "Implementation Plan for Comprehensive 54 Prevention and Control of Myopia among Children and Adolescents" on 30 August 2018, and 55 jointly with the government, schools, medical and health institutions, families and students, 56 which aims to reduce the overall myopia prevalence among children and adolescents 57 nationwide by more than 0.5% per year by 2023 from the 2018 level, and reduce it by more 58 than 1% per year in provinces with a high prevalence of myopia. In addition, it is expected that 59 by 2030, the myopia prevalence will be controlled at around 3% among 6-year-old children and 60 will be reduced to less than 38% among primary school students, less than 60% among junior 61 high school students, and less than 70% among senior high school students. 62 It is important to note that the development of myopia is a dynamic process. Myopia prevention 63 requires intervention prior to the onset of myopia, which needs to define the "premyopia state", 64 i.e., a refractive state that is temporarily emmetropia, with normal visual acuity and refractive  Low-level red-light therapy has been widely used for neurotrauma and stroke, and provides an 83 innovative, non-invasive treatment for severe vision-impairing eye diseases such as 84 age-related macular degeneration, amblyopia, diabetic retinopathy and Leber hereditary optic 85 neuropathy. 12,13 Some studies have suggested that the mechanism of low-level light therapy 86 does not rely on the thermal effect of conventional light therapy, but rather on the 87 photochemical conversion potential of low-level red-light, which could induce photochemical 88 reactions in ocular tissues, increase cytochrome C oxidase activity, alter gene expression to 89 regulate the mitochondrial respiratory chain, and increase the biological activity of nitric 90 oxide. 14-18 We hypothesize that low-level light therapy can increase choroidal metabolic rate 91 and circulation through the above-mentioned mechanisms, thereby improving scleral hypoxia 92 and preventing the development and progression of myopia. 93 Preliminary results from the multi-center study led by our hospital suggested that low-level 94 single-wavelength red-light was a safe intervention which did not cause detectable functional 95 damage to the retina or macula, while significantly reducing the progression of myopia. This 96 real-world study will for the first-time focus on typical primary schools to investigate the 97 feasibility and effectiveness of low-level red-light therapy in reducing the prevalence of myopia 98 in schools by preventing myopia in premyopic school-aged children. If the study is successful, 99 it will provide new insights for comprehensive myopia prevention and control among children 100 and adolescents. 101 102

Study purpose 103
Children aged 6-11 years old who meet the inclusion criteria in selected schools in Shanghai 104 are include. A one-year randomized controlled trial is conducted to investigate the efficacy of 105 repeated low-level red-light (RLRL) of preventing myopia onset and reducing its incidence. 106 107

Study design 108
To investigate the effects of RLRL on preventing myopia onset and reducing the incidence of 109 myopia, several primary schools in Shanghai will be selected as participating schools in this 110 study. Children from grades 1-4 in participating schools with non-cycloplegic spherical 111 equivalent refraction (SER) < 1.0 and uncorrected visual acuity > 0.8 are first screened based 112 on refractive screening data. These children then answer the questionnaire and undergo 113 cycloplegia and those with -0.5 < cycloplegic SER of worse eye <= +0.5 D and at least one 114 parent with myopia (at least one eye SER <=-3.0 D) were included. Participants are stratified 115 by grade and randomized into an intervention group and a control group at the ratio of 1:1. 116 The intervention is implemented according to the following steps: In the intervention group, 117 subjects receive RLRL interventions in a temporary intervention room at school twice per day 118 from Monday to Friday (each intervention lasts 3 minutes with an interval of at least 4 119 hours).No RLRL intervention will be performed in the control group. 120 For the enrolled schools, standard screenings will be completed at baseline (in April 2021).

Study site 129
Children aged 6-11 years who meet the inclusion criteria from grades 1-4 in selected primary 130 schools will be enrolled as participants. Myopia examination will be conducted at 5 time points 131 to determine the incidence and prevalence of myopia. 132 Temporary intervention rooms will be set up in the participating schools with a sufficient 133 number of red-light intervention devices. Children with premyopia are identified according to 134 the inclusion and exclusion criteria, and then randomized by grade within each school, and 135 divided into intervention and control groups. RLRL will be implemented in the intervention 136 group.

Implementation of intervention measures 156
Red-light intervention: 157 The intervention in this study is repeated low-level single-wavelength red-light, which was 158

Compliance management 263
The coordinator shall uniformly manage and solve the problems encountered by students 264 during operation, and at the same time supervise and record the relevant interventions. 265 Through the user account, count the number of backstage usage every week, carry out joint 266 supervision with the coordinator, and randomly check the work of the coordinator to urge him 267 to complete the recording and coordination work on time and quality. 268 269

Sample size calculation 270
This study is a real-world study based on selected elementary schools in Shanghai, and the 271 sample size was calculated according to the district group randomization formula with the 272 following parameter settings: according to the data from previous studies, the average annual 273 myopia incidence for elementary school students in grades 1-4 is 42%, and it is expected that 274 the use of low-level single-wavelength red-light in schools can reduce the incidence of myopia 275 by 50%, i.e., the incidence of myopia decreases to 21%. A total of 202 students are required 276 based on a test efficacy of 90% and α=0.05. Considering a participation rate of 90% and a 277 missed visit rate of less than 10% per year, a total of 254 individuals would be required. 278 279

Recruitment 280
Some primary school children in Shanghai will be invited to participate in this study. First, 281 school-age children in grades 1-4 in participating schools will be screened for non-cycloplegic 282 spherical equivalent (SE) less than 1.0 D and UCVA > 0.8 based on refractive developmental 283 profile data and undergo cycloplegia. Those with -0.5 D < cycloplegic SE of worse eye ≤ +0.5 284 D and at least one parent has myopia (SER <=-3.0D) will be selected and the intervention and 285 control groups were formed according to the intra-school matched-grade individual 286 randomization method. 287 288 289

Randomization 291
To avoid bias, The study will use a computer system centrally controlled randomization method 292 to achieve central randomized grouping. 293 294

Allocation concealment 295
After the investigators in each center access the server through the web and enter the 296 information of individuals, the computerized randomization system will divide the individuals 297 according to the random assignment table and lock the division information of individuals in the 298 system. 299 300

Allocation implementation 301
In the central randomization system, the statistical expert in charge of randomization designs 302 the randomization parameters in advance in the background, and the system generates the 303 random assignment table. 304 305

Blinding 306
In this study, the grouping and other information will be concealed from the eye examiners and 307 data analysts, and a single blind is set up. 308 309 310 4 Data collection, management, and analysis 311

Data collection 312
The examination consists of one baseline and four follow-up examinations. Detailed content or 313 description are described as follows: 314 1) Registration: Name, date of birth, gender, ethnicity, contact information, school and class 315 information. conjunctiva, cornea, anterior chamber, iris, pupil, lens, and anterior vitreous body, and is 333 performed by senior experienced ophthalmologists. Those with peripheral anterior chamber 334 depth less than 1/2 corneal thickness, or those who have acute anterior segment inflammation, 335 or other related diseases, and are not suitable for further cycloplegia, will be recorded. Either 336 will the examination be suspended, or they be excluded from this study. In addition, methods 337 such as corneal light reflection, cover-uncover, etc. are used for strabismus detection and 338 typing (phoria or manifest strabismus). Those with manifest strabismus will be excluded. The values. The raw data captured by the equipment will be uploaded simultaneously via the 377 collection device provided by the project. Upon completion of the examination, paper 378 examination forms will be kept in a locked cabinet in the research center to protect the privacy 379 of the participants and to locate and check the raw data. 380 381

Statistical analysis plan 382
The aim of this study was to investigate the effect of low-level single-wavelength red-light on 383 prevent myopia and reduce the incidence of myopia in schools. Myopia in this study is defined 384 as equivalent spherical (SE) < -0.50 D based on cycloplegic autorefraction results.

386
Data analysis will be performed under the intention-to-treat (ITT) and and per-protocol (PP) 387 principle. All subjects who complete the protocol and those who fail to complete the protocol 388 but do not withdraw from the study will be included in the analysis. For subjects who withdraw 389 from the study, valid data collected before withdrawal will be included in the analysis data set.

391
The primary outcome is the incidence of myopia, and secondary outcomes are the progression 392 of SE, AL, UCVA, BCVA, and CT. 393 394 To compare the incidence of myopia in the intervention and control groups, a chi-square test 399 will be used. For statistical analysis based on other secondary outcomes, the data from the 400 worse eye will be taken for analysis. If quantitative traits conform to a normal distribution, the 401 significance will be tested according to an unpaired t-test. If they do not conform to a normal 402 distribution, the significance will be tested by non-parametric statistical methods or by taking 403 cut-off points according to clinical significance, calculating the proportions of categorical 404 variables and testing significance by chi-square tests.

406
Sensitivity analyses based on the protocol strategy will be performed to investigate the efficacy 407 of repeated low-level red light therapy on primary outcome and secondary outcomes. 408 Sensitivity analyses will be further performed to assess efficacy of repeated low-level red-light 409 therapy across different refraction groups and age groups. and Safety Committee regularly review the data collection process, storage, and analysis, and 416 have access to the raw data associated with this clinical study to determine the completeness, 417 accuracy and consistency of the information with the original data holdings. Relevant 418 information needs to be readily available to members of the Data and Safety Committee. The 419 Data and Safety Committee Board is required to review all data and informed consent. 420 421

Risks/hazards (adverse reactions) 422
The intervention used in this study is the Eyersing Amblyopia Intervention Device, which has 423 received a national safety test certificate, and a Class II medical device registration certificate, 424 and the manufacturer has a medical device manufacturing license. The intervention device 425 has been marketed and is widely used in major hospitals. It has been used clinically for more 426 than ten years in the field of amblyopia treatment and has no known side effects on the 427 structural function of the eye. The intervention device uses a diode to produce a single 428 wavelength of visible red light at 650±10 nm, reaching the eye with an energy range of 1.07 to 429 Requirements", radiation is safe for use in the eye. After using the intervention device, there 433 may be a temporary reaction of dazzling, flash blindness, and post-optical light spots, which 434 may resolve themselves after a few minutes of rest with eyes closed. 435 436

Audit 437
An auditing team independent of the sponsor is set up by the investigator to visit each school 438